Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers
Stuckey, J. I.; Mertz, J. A.; Wilson, J. E.; Williamson, K. E.; Li, Y.; Kuljanin, M.; DeLaBarre, B.; Chenail, G.; Nguyen, P. A.; Bailey, C. M.; Motley, W. M.; Audia, J. E.; Sims, R. J.
Show abstract
We report our mechanistic investigation into the conformationally-driven activation bias of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG inverse agonism. We utilized studies into tumor-associated mutations in both PPARG and RXRA, as well as a combination of structure-based drug design merged with insights from biochemical mechanistic studies to discover FX-909, a first-in-class clinical PPARG inverse agonist that robustly enforces a conformationally repressive state of PPARG, even in highly activated contexts such as RXRA S427F mutation and PPARG amplification. FX-909 is a potent, highly selective, and powerful suppressor of PPARG transcriptional activity through enhancement of PPARG nuclear corepressor binding (NCOR) affinity. Treatment with FX-909 resulted in selective growth inhibition in PPARG-activated MIUC cell lines. Further, FX-909 achieved durable regressions in xenograft models of MIUC through inverse agonism of PPARG. FX-909 is the first chemical tool available to the community that is capable of recapitulating PPARG genetic knockout in vivo and is currently in clinical development for the treatment of intractable MIUC.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Inhibition of constitutive activity of the atypical chemokine receptor ACKR3 by the small-molecule inverse agonist VUF16840 95%
- Cannabinoid Receptor 2 Activating Antibodies: A Promising Therapeutic Strategy for Macrophage-Driven Fibro-Inflammatory Diseases 95%
- Pharmacological characterization and radiolabeling ofVUF15485, a high-affinity small-molecule agonist for theatypical chemokine receptor ACKR3 94%
Similar papers in this journal
- Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states 97%
- Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells 95%
- Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies 95%
Similar papers in this journal
- The orphan ligand, Activin C, signals through activin receptor-like kinase 7 95%
- Stereo-specific Lasofoxifene Derivatives Reveal the Interplay between Estrogen Receptor Alpha Stability and Antagonistic Activity in ESR1 Mutant Breast Cancer Cells 95%
- Molecular basis of ligand-dependent Nurr1-RXRα activation 95%
Similar papers in this journal
- CRISPR/Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells 93%
- A Novel, Uniquely Efficacious Type of CFTR Corrector with Complementary Mode of Action 93%
- Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leads 93%
Similar papers in this journal
- Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes 93%
- Therapeutic assessment of targeting ASNS combined with L-Asparaginase treatment in solid tumors and investigation of resistance mechanisms 93%
- An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.